Corticotropin Releasing Factor (CRF) was a peptide comprising 41 amino acid residues and isolated from ovine hypothalamic in 1981. It was suggested that CRF was released from hypothalamic and controlled a secretion of adrenocorticotropic hormone (ACTH) from hypophysis [Science, 218, 377-379 (1982)].
ACTH, which is released by a stimulation of CRF, stimulates a secretion of cortisol from adrenal cortex, and relates to a systemic action for reproduction, growth, gastrointestinal function, inflammation, immune system, nervous system etc. Consequently, CRF is believed to play a role as a regulator of these functions. In view of these, a relationship of CRF and a central nervous system disease or a neuropsychiatric disorder has gained a lot of attention.
In WO 02/053565, a compound of formula (A)

wherein XA and YA each, independently, is carbon or nitrogen and both are not nitrogen at the same time; WA is carbon or nitrogen; UA and ZA each, independently, is CR2A, NR13A, nitrogen, oxygen, sulfur, C═O or C═S;
R2A is (i) hydrogen, (ii) C1-8 alkyl, (iii) C2-8 alkenyl, (iv) C2-8 alkynyl, (v) halogen atom, (vi) CF3, (vii) cyano, (viii) nitro, (ix) NR9AR10A, (x) OR11A, (xi) SH, (xii) S(O)nAR12A, (xiii) COR11A, (xiv) COOR11A, (xv) CONR9AR10A, (xvi) C3-10 mono- or bi-carbocyclic ring, (xvii) 3- to 10-membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) or (xviii) substituted C1-4 alkyl;
 is a single bond or a double bond;
is C4-6 carbocyclic ring or 4-6 membered heterocyclic ring containing at least one of nitrogen, oxygen and sulfur and these rings are unsubstituted or substituted by 1-3 of substitutes selected from C1-4 alkyl, C1-4 alkoxy, halogen atom and CF3;
R1A is (i) unsubstituted or substituted C1-8 alkyl, (ii) unsubstituted or substituted C2-8 alkenyl, (iii) unsubstituted or substituted C2-8 alkynyl, (iv) NR4AR5A, (v) OR6A, (vi) SH, (vii) S(O)nR7A, (viii) COR6A, (ix) COOR6A, (x) CONR4AR5A, (xi) NR8ACOR6aA, (xii) NR8ACOOR6A, (xiii) NR8ACONR4AR5A, (xiv) unsubstituted or substituted C3-15 mono- or bi-carbocyclic ring, (xv) unsubstituted or substituted 3-15 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s);
was described as CRF receptor antagonist.
In addition, in WO 02/053565, 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidine hydrochloride was described.
As an intermediate of the compound of formula (A), a compound of formula (B) was described:

wherein R2A-a is (i) hydrogen, (ii) C1-8 alkyl, (iii) C2-8 alkenyl, (iv) C2-8 alkynyl, (v) halogen atom, (vi) trifluoromethyl, (vii) cyano, (viii) nitro, (ix) NR9AR10A, (x) OR11A, (xi) SH, (xii) S(O)nR12A, (xiii) COR11A, (xiv) COOR11A, (xv) CONR9AR10A, (xvi) C3-10 mono- or bi-carbocyclic ring, (xvii) 3- to 10-membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) or (xviii) substituted C1-4 alkyl, with the proviso that R2A-a is not OH, cyano, ═N—OR11A, or a group containing OH, cyano or ═N—OR11A,
R3A-a is (i) substituted C5-10 mono- or bi-carbocyclic ring, or (ii) substituted 5-10 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s), with the proviso that these above groups are not OH, cyano, ═N—OR11A, or a group containing OH, cyano or ═N—OR11A.
In the compound of formula (B), 1-cyano-1-(2-methyl-4-methoxyphenyl)propan-2-one (Compound B-1), and 1-cyano-1-(2-chloro-4-methoxyphenyl)propane-2-one (Compound B-2) were described as Reference Examples, and it was shown that these compounds may be produced by a process described in scheme A and B.

[Process a] is carried out by the reaction of 1,2-dimethyl-4-methoxybenzene with N-bromosuccinimide and 2,2′-azobisisobutylonitrile, and then carried out by a reaction of the obtained compound and sodium cyanide.
[Process b] is carried out by the reaction of the compound prepared in [process A] and metallic sodium, in ethyl acetate.
[Process c] is carried out by the reaction of 3-chloro-4-bromoanisol and triisopropyl borate, in tetrahydrofuran, in the presence of n-butyl lithium.
[Process d] is carried out by the reaction of the compound prepared in [process c] and 4-iodo-5-methylisoxazole, in a mixture of dimethoxyethane/water, in the presence of sodium carbonate and tetrakis(triphenylphosphine)palladium.
[Process e] is carried out by the reaction of the compound prepared in [process d] and sodium methoxide, in methanol.
In WO 02/053565, as a concrete compound, 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidine hydrochloride was described. However, the thermal stability of this compound was poor. It separated and escape of hydrochloric acid occurred above a certain temperature. In addition, crystallinity of this compound was poor, and a yield of the crystal was very low.
As described above, it was difficult to provide stability to the hydrochloride compound possessing characteristics of inferior thermal stability and a low yield of crystal. Additionally, a problem may be caused if a heating process is necessary in the production of drug products, therefore, the hydrochloride compound was undesirable as a pharmaceutical drug substance.
Further, in the process for the preparation of the intermediate of formula (B) described above, the reaction of [process b] using metallic sodium in scheme A required specialized equipment under strong alkali condition, so it was not adequate for industrial production. Additionally, a total yield of the compound B-1 in the two processes of [process a] and [process b] was low, in particular 59%.
In the reaction of scheme B, 4-iodo-5-methylisoxazole used in [process d] was not adequate for industrial production. The reason is that procurement of methyl isoxazole, which is the starting material for 4-iodo-5-methylisoxazole, was difficult. Additionally, three processes were needed to produce the compound B-2, and a total yield was low, in particular 27%.
As described above, the preparation process described in WO 02/053565 has some problems, for example, a lot of processes, a low yield of the objective compound and inferior industrial productivity.
The present inventors have made extensive studies to solve the above problems, and as a result, have found that the object is achieved by a novel compound of 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidine methanesulfonate and a novel crystal thereof.
Additionally, the present inventors have discovered a process for the preparation of a compound of formula (I)

wherein all symbols are as hereinafter defined,
which could be prepared by reacting the compound of formula (II)Ar—X  (II)
wherein all symbols are as hereinafter defined,
and a compound of formula (III)

wherein all symbols are as hereinafter defined,
in the presence of a homogeneous catalyst.
The compound of formula (I) was an intermediate of 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidine methanesulfonate which is useful for pharmaceuticals, and the process was one step and efficient. Also the objective compound was possible to obtain in high yield.